There are several Gram-positive species that cause diseases in humans. The most common organisms include Staphylococcus, Streptococcus, Enterococcus, Clostridium, Bacillus, Corynebacterium, and Listeria species. Infections with common Gram-positive organisms have become more problematic to treat because of the growing trend of antibiotics drug-resistance.
Examples of such difficult-to-treat resistant bacteria include methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae (PRSP), and vancomycin-resistant Enterococcus (VRE).
Staphylococcus aureus can cause a range of illnesses such as pimples, impetigo, boils, cellulitis folliculitis, furuncles, carbuncles, scalded skin syndrome, pneumonia, meningitis, osteomyelitis, endocarditis, toxic shock syndrome and sepsis. S. aureus is one of the most common causes of hospital-acquired infections. Streptococcus pneumoniae can cause many types of infections such as community acquired pneumonia, bronchitis, rhinitis, acute sinusitis, otitis media, conjunctivitis, meningitis, bacteremia, sepsis, osteomyelitis, septic arthritis, endocarditis, peritonitis, pericarditis, cellulitis, and brain abscess. Enterococcus can cause urinary tract infections, bacteremia, endocarditis, diverticulitis, and meningitis.
Clostridium difficile infection (CDI) is another problematic Gram-positive bacterial infection. CDI-related death has increased due to the spread of a hyper virulent NAP1/027 strain. Current treatments lead to more than 23% recurrence and have limitations against this virulent strain.
Haemophilus influenzae, a Gram negative bacteria, can cause many kinds of infections including, but not limited to, ear infections, bacteremia, community-acquired respiratory infections, pneumonia and acute bacterial meningitis.
Treatment of bacterial infectious diseases is becoming more difficult and expensive due to developing resistance to existing antibiotics, spreading hypervirulent strains, and non-availability of more efficatious novel antibacterial agents.
In view of the above facts, the inventors of the present invention have realized that there should be a novel class of antibacterial agent having novel mechanism of action. After exhaustive research, the inventors of the present invention have discovered novel compounds targeting the DNA gyrase GyrB subunit and/or topoisomerase IV ParE subunit, and hence are ready to meet the requirements of millions of patients worldwide.
In developing antibiotics having a novel mechanism of action, synthetic inhibitors targeting the DNA gyrase GyrB subunit are known in the art. For example, WO 2005/026149 (PTL 1), WO 2006/087543 (PTL 2), WO 2006/087544 (PTL 3), WO 2006/087548 (PTL 4), WO 2006/092599 (PTL 5), WO 2006/092608 (PTL 6), WO 2008/152418 (PTL 7), WO 2008/020222 (PTL 8), WO 2008/020227 (PTL 9), WO 2008/020229 (PTL 10), WO 2010/013222 (PTL 11), WO 2010/067123 (PTL 12), and WO 2010/067125 (PTL 13) describe pyrrole derivatives having antibacterial activity. WO 2007/071965 (PTL 14) describes bicyclic heteroaromatic compounds. WO 2014/057415 (PTL 15) describes quinoline based compounds. These compounds had the problems of insufficient activity, low water solubility and toxicity. In addition, none of the cited references disclosed imidazole derivatives.
WO 2009/084614(PTL 16), incorporated herein by reference in its entirety, describes imidazole derivatives. The compounds disclosed in WO 2009/084614 have good properties, for example, sufficient in vitro antibacterial activity and no cytotoxicity. However, Compound No. 150 having a thiadiazole substituent had a problem of not being efficacious in animal infection models, hence not suitable for use in human.

On the contrary, the hydroxyalkyl thiadiazol derivative thereof, in which the thiadiazole moiety of said compound is modified to be substituted with hydroxyalkyl substitutents have been revealed to have sufficient solubility for oral absorption. The structure of said hydroxyalkyl thiadiazole derivative is represented by the following general formula (1′):

wherein R represents (C1-C3) alkyl, and
A represents the following formulae:

provided that, in the general formula (1′), for example, tautomers with a hydrogen at different positions of the imidazole ring are included.
In more detail, the following compounds are included therein as more preferable compounds:

wherein R represents (C1-C3) alkyl, and
A represents the following formulae:

Surprisingly, said hydroxyalkyl thiadiazole compounds of the general formula (1′) showed not only sufficient in vitro antibacterial activity, no cytotoxicity, good water solubility for oral absorption, but also remarkably good efficacy and safety, and hence are suitable for use in humans. The present invention describes N-phosphonoxymethyl prodrugs of the hydroxyalkyl thiadiazole compound of the general formula (1′), preferably for oral or intravenous use.
Thus, the present invention provides great hope for a new antibiotic to meet the challenges of a serious global health concern due to problematic bacteria thereof causing bacterial infections, for example, but not limited to, community-acquired respiratory infections, hospital-acquired infections, urinary tract infections, and Clostridium difficile infections.